Venkadesh Sarkarai Nadar

Project Title: A potential novel arsenic-containing anti-cancer drug for triple-negative breast cancer (TNBC)

The overall goal of this project is to evaluate the potential of a newly identified arsenic-containing drug, arsinothricin (2-amino-4-(hydroxymethylarsinoyl) butanoate or AST), as an anticancer agent by inhibition of glutaminase. Cancer is the second leading cause of death in the United States. According to the National Cancer Institute (NCI) African American women are diagnosed with triple-negative breast cancer (TNBC) at more than twice the frequency of other racial or ethnic groups of women. Epidemiological, clinical and preclinical data reveal that both biological and socioeconomic causes contribute to this cancer disparity, as does the aggressive progression of the disease and the lack of targeted therapies. Thus, targeted anti-cancer drugs for TNBC are urgently needed. AST is a natural product produced by soil bacteria and is an effective broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria with low cytotoxicity to human cells.  We have shown that its mechanism of action is as a potent inhibitor of the essential enzyme glutamine synthetase. It is reasonable to assume that AST can target other enzymes with glutamine as a substrate or product. The central hypothesis of this pilot is that AST inhibits glutaminase (GLS), the enzyme that controls glutamine metabolism is correlated with tumor malignancy. TNBC cells utilize glutamine as a primary source of energy and inhibition of GLS significantly hinders cancer cell growth and proliferation. For this reason, GLS has been a major target for development of anticancer drugs for TNBC. The results of this study have the potential to lead to the development of a new potent anticancer drugs for treatment of triple-negative breast cancer.

Research Interests

X-ray Crystallography, Protein structure and function, Arsenic biotransformation, Anti-cancer drug discovery

Department of Cellular Biology and Pharmacology
Herbert Wertheim College of Medicine

Venkadesh Sarkarai Nadar is an instructor in Cellular Biology and Pharmacology at Herbert Wertheim College of Medicine at Florida International University. He received a B.Sc. (2002) and M.Sc. (2005) in physics from Madurai Kamaraj University and Alagappa University respectively in Tamil Nadu, India. He received his Ph.D. degree (2011) in Crystallography and Biophysics from the University of Madras, Chennai, India. The objective of his Ph.D. work was to design the oligonucleotide sequences that form a four-way junction and characterize them using various biophysical methods. After completion of his Ph.D., in 2012, he joined Dr. Barry P. Rosen’s laboratory in Department of Cellular Biology and Pharmacology, HWCOM, FIU, Miami as postdoctoral associate in 2013 and is now working as an instructor. His research interest is to elucidate the mechanism of enzymes which involve for the arsenic biotransformation using different biophysical techniques, exclusively X-ray crystallography. He crystallized and solved the three-dimensional structure of ArsI C-As lyase, a carbon arsenic bond cleaving enzyme from the thermophilic bacterium Thermomonospora curvata and a novel enzyme, ArsN Arsinothricin N-acetyltransferase from Pseudomonas putida KT2440.

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